Journal of Clinical Anesthesia (2006) 18, 422 426 Original contribution Dexmedetomidine infusion is associated with enhanced renal function after thoracic surgery Robert J. Frumento MS, MPH, Helene G. Logginidou MD, Staffan Wahlander MD, Gebhard Wagener MD, Hugh R. Playford MBBS, FANZCA, FJFICM, Robert N. Sladen MBChB, MRCP(UK), FRCP(C) (Professor and Vice Chair)* Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA Received 12 October 2005; revised 16 December 2005; accepted 1 February 2006 Keywords: Analgesia; Epidural; Dexmedetomidine; Fluid restriction; Intraoperative; Glomerular filtration; Renal function; Thoracic surgery; Thoracotomy Abstract Study Objective: To test the hypothesis that dexmedetomidine, a selective a-2 agonist, enhances urine flow rate and perioperative renal function, a post hoc analysis was conducted on a recently completed study of dexmedetomidine used as an adjunct to epidural analgesia after thoracotomy. Design: Post hoc analysis of a randomized, placebo-controlled, double-blind clinical trial. Setting: Tertiary-care university medical center. Patients: 28 patients undergoing elective thoracotomy. Interventions: Patients were prospectively randomized to receive a supplemental 24-hour intravenous infusion of either dexmedetomidine (0.4 lg kg 1 h 1, n = 14) or saline placebo (equivalent infusion rate, n = 14). Measurements: Available renal parameters including urine output, calculated creatinine clearance (ccl Cr ), daily serum creatinine level (S Cr ), and the fractional change in S Cr level (DS Cr %, [peak postoperative S Cr baseline S Cr ] / baseline S Cr ) 100) were recorded. Main Results: Values are expressed as means F SD. There were no significant differences in baseline values between the groups. The dexmedetomidine group had significantly greater cumulative urine output at postoperative hour 4 (473 F 35 vs 290 F 122 ml, P = 0.001) and 12 (1033 F 240 vs 822 F 234 ml, P = 0.02), although only 14% of the group received diuretic agents, compared with 43% in the control group. The dexmedetomidine group had significantly better preserved perioperative renal function compared with the control group, as assessed by DS Cr % (0.04% decrease vs 21% increase, P = 0.0007) and ccl Cr (75.3 F 13.2 vs 62.5 F 15.5 ml/min, P = 0.02). Conclusion: Dexmedetomidine infusion administered as a supplement to epidural analgesia induced diuresis in postthoracotomy patients with normal preoperative renal function and undergoing fluid restriction. Although this finding may represent simple reversal of a tubular antidiuresis, the lower DS Cr % and preservation of ccl Cr suggest a beneficial effect on glomerular filtration compared with controls. D 2006 Elsevier Inc. All rights reserved. * Corresponding author. Tel.: +1 212 305 8633; fax: +1 212 305 8287. E-mail address: rs543@columbia.edu (R.N. Sladen). 0952-8180/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2006.02.005
Dexmedetomidine in thoracic surgery 423 1. Introduction Patients undergoing thoracic surgery are managed with intentional fluid restriction to minimize extravascular lung water. Moreover, this population of patients is steadily aging, with increasing cardiac and renal comorbidity [1]. Although the incidence of acute renal failure is relatively low, both it and renal dysfunction without failure are associated with high morbidity and mortality [2]. Interventions that may preserve renal function in this patient population are therefore desirable. Dexmedetomidine is a selective a-2 agonist that provides anxiolysis and analgesia without respiratory depression [3,4]. It has clinically significant sympatholytic properties [5] and decreases the stress response to surgery and intensive care procedures [6,7]. In animal models involving general anesthesia, dexmedetomidine increases urinary output while decreasing urine osmolality and increasing free water clearance, suggesting that it reverses a prerenal antidiuretic response [8]. However, in a large multicenter study of intensive care unit (ICU) sedation after coronary artery bypass graft surgery, dexmedetomidine increased diuresis and decreased the incidence of high serum creatinine (S Cr ) values [9], suggesting a possible benefit on glomerular filtration. To further test these hypotheses, we performed a post hoc analysis on renal function in patients who had participated in a recently completed study of dexmedetomidine used as an adjunct to epidural analgesia after thoracotomy [10]. 2. Materials and methods After institutional review board approval and written informed consent, 28 patients undergoing thoracotomy were studied. In all patients, a thoracic epidural catheter was placed by loss-of-resistance technique and was tested before induction of general anesthesia. No further medication was given via the epidural catheter until the end of the operation. General anesthesia was induced with intravenously (IV) administered propofol, fentanyl, and rocuronium, and a Table 1 Patient characteristics Characteristic Placebo group (n = 14) Dexmedetomidine group (n = 14) Age (y) 65.7 F 10.3 65.7 F 9.0 Weight (kg) 69.8 F 7.5 69.9 F 6.3 Height (cm) 167.6 F 8.6 168.9 F 9.1 Gender (% men) 43 43 Race (% Caucasian) 86 79 Diabetes (%) 43 50 Hypertension (%) 57 64 COPD (%) 57 43 Data are means F SD. No significant differences between groups were noted. COPD indicates chronic obstructive pulmonary disease. Table 2 Patient demographic data Placebo group (n = 14) double-lumen endotracheal tube was placed to facilitate lung isolation. Anesthesia was maintained with nitrous oxide in oxygen (nitrous oxide was withheld during lung isolation), isoflurane, fentanyl, and rocuronium as required. Standard monitoring was provided including an indwelling radial artery catheter. At the end of the surgical procedure, all patients were allowed to emerge and underwent tracheal extubation. Immediately after the arrival in the ICU or postanesthesia care unit, all patients had their thoracic epidural catheter loaded with 0.125% bupivacaine to establish a pain score of less than or equal to 3 on the Visual Analog Scale. Patients were then randomized into one of two groups. The dexmedetomidine group (n = 14) received a loading dose of 0.5 lg/kg dexmedetomidine for 20 minutes followed by a continuous IV infusion at 0.4 lg kg 1 h 1 for 24 hours. The placebo group received a loading dose and continuous IV infusion of saline at the same rate. A detailed description of this study and the outcome regarding analgesia is published elsewhere [10]. We performed a post hoc analysis of perioperative renal function. Cumulative urine volume was documented at 4 and 12 hours after surgery. We calculated creatinine clearance (ccl Cr ) at the same time points by using the Cockroft-Gault equation, which incorporates gender, age, weight, and S Cr [11]. The change in perioperative renal function was assessed by peak serum creatinine clearance (S Cr ) measured within the first week postoperatively (7-day peak) and expressed as the fractional change in S Cr (DS Cr %), as follows: peak postop S Cr baseline S Cr baseline S Cr 100% Dexmedetomidine group (n = 14) Procedure Lobectomy 12/14 (86%) 12/14 (86%) Pneumonectomy 2/14 (14%) 2/14 (14%) Intraoperative data Procedure length (min) 183 F 36 191 F 40 Crystalloid 712 F 162 698 F 113 administered (ml) EBL 169 F 61 187 F 62 Urine output (ml) 310 F 42 290 F 61 Fluid balance (ml) +233 F 89 +221 F 99 ICU (first 24 h) Crystalloid 720 F 92 679 F 101 administered (ml) Fluid balance 190 F 77 201 F 88 Diuretic administered 6/14 (43%) 2/14 (14%) NSAID administered 3/14 (21%) 2/14 (14%) Data are means F SD. No significant differences between groups were noted. EBL indicates estimated blood flow; NSAID, nonsteroidal antiinflammatory drug.
424 R.J. Frumento et al. Fig. 1 Urine output. POD1 indicates postoperative day 1; DEX, dexmedetomidine; *P b 0.05, compared with placebo for same time point. where peak postop S Cr is the peak value of S Cr within the first 7 postoperative days and baseline S Cr is the last preoperative S Cr. 2.1. Statistical methods Data are summarized as means F SD for continuous variables and percentages for categorical values. A P value b0.05 was considered statistically significant. Tukey s method (for multiple comparisons of group means) was used to assess pairwise group differences. Differences between categorical variables were tested using v 2 or Fishers exact tests, as appropriate. 3. Results A total of 28 patients were included in the final analysis, 14 in the dexmedetomidine group and 14 in the control group. The study groups were similar with respect to all demographic (Table 1) and perioperative factors (Table 2), including age, weight, baseline S Cr, surgical procedure, and comorbidity. Patients in the dexmedetomidine group had significantly greater cumulative urine output than the control group at Fig. 2 Change in serum creatinine clearance over time. POD indicates postoperative day; *P b 0.05, compared with placebo for same time point. Fig. 3 Change in calculated creatinine clearance (ccl Cr ). *P b 0.05, compared with placebo for same time point. postoperative hour 4 (473 F 135 vs 290 F 122 ml, P = 0.001) and hour 12 (1033 F 240 vs 822 F 234 ml, P = 0.02) (Fig. 1). Diuretic agents were administered to only two of 14 patients in the dexmedetomidine group compared with 6 of 14 patients in the control group (14% vs 43%, nonsignificant). Systolic blood pressure (BP) and heart rate were significantly lower in the dexmedetomidine group compared with the control group at every hour during the 24-hour study period ( P b 0.05, data not shown). Postoperative S Cr was significantly lower in the dexmedetomidine group compared with control 24 hours after surgery, and this difference remained significant throughout the hospital stay (Fig. 2). Patients in the dexmedetomidine group also had significantly lower DS Cr % (0.04% decrease vs 21% increase in the control group, P = 0.0007) and increased ccl Cr (Fig. 3). 4. Discussion In this post hoc analysis of postoperative thoracic surgical patients without renal disease, we observed a significant association between dexmedetomidine infusion and improved postoperative renal function, including indices of glomerular filtration (S Cr,Cl Cr ), as well as urine flow rate. In an effort to restrict the accumulation of extravascular lung water, patients undergoing thoracotomy are quite severely fluid restricted in the perioperative period. This situation creates a prerenal state of salt and water retention, which, in concert with the sympathoadrenal stress response to surgery, may induce renal injury. The thoracic surgical population is steadily aging, with a concomitant increase in the incidence of underlying cardiovascular disease. For example, patients with non small cell lung cancer presenting for surgical resection have a higher burden of comorbidity than do patients with tumors of other sites, such as breast, prostate, colon, and head and neck [1]. After thoracotomy, the incidence of postoperative acute renal failure requiring dialysis is relatively low (1.2%- 4.5%), but when it occurs morbidity and mortality are
Dexmedetomidine in thoracic surgery 425 markedly increased [12,13]. The incidence of renal dysfunction without overt failure is considerably higher, and it too can substantially increase morbidity and mortality [13]. Golledge and Goldstraw [2] documented renal impairment in 24% of 130 consecutive patients undergoing major thoracotomy. Its development increased hospital length of stay by 50% and increased mortality from zero to 19%. Our data show that patients who received dexmedetomidine as part of their analgesic regimen had significantly greater urine output for the first 24 hours after surgery. This occurred despite equivalent fluid administration and the fact that more patients in the placebo group were given diuretic therapy. A possible mechanism for this finding is that dexmedetomidine decreases the release and/or the antidiuretic effect of arginine vasopressin (AVP). In a study on canines, administration of two lg/kg dexmedetomidine to anesthetized dogs doubled urine flow from 30 to 60 ml/h and was associated with both a decreased urine osmolality and plasma AVP [8]. However, we are unable to confirm this hypothesis in the present retrospective analysis because we did not measure changes in urine osmolality or plasma AVP. Perhaps of more clinical importance is our observation that S Cr was significantly decreased in the dexmedetomidine group and that this decrease was sustained for up to a week after surgery. This finding suggests that dexmedetomidine administration may have had a salutary effect on glomerular filtration that persisted for some time after the drug itself was discontinued. A decrease in S Cr in the dexmedetomidine group has been noted in passing in the discussion section of at least two other prospective trials of postoperative sedation, but no details were given [7,9]. The potential mechanisms of benefit of dexmedetomidine on glomerular filtration remain speculative at this stage. It is conceivable that dexmedetomidine-induced decreases in BP may have forced the administration of greater quantities of IV fluid, with improved renal perfusion. However, there were no differences noted in the quantity of crystalloid administered to the two groups. A more plausible explanation is that the administration of dexmedetomidine is associated with decreased renal vasoconstriction. a-2 Agonists activate a-2b receptors in the locus caeruleus near the fourth ventricle of the brain, and centrally decrease circulating plasma norepinephrine in a dose-related manner. In contrast, peripheral stimulation of a-2c receptors in the wall of vascular smooth muscle causes vasoconstriction and increased systemic vascular resistance, a phenomenon observed during rapid loading of dexmedetomidine or infusion of very high doses [14]. However, with continuous infusion in the usual dose range (0.2-0.7 lg kg 1 h 1 ) the central effect predominates and BP (and heart rate) are decreased by about 15% to 20%, as was seen in our study. It is therefore conceivable that because dexmedetomidine attenuates stress-induced increases in circulating norepinephrine, it may maintain renal blood flow and glomerular filtration. Indeed, it is well established that the administration of a-2 adrenergic agonists can inhibit the surgical stress response [15-17] and thereby protect the kidney against the detrimental effects of adrenergic-mediated vasoconstriction [18]. There also may be direct vascular effects in the kidney. Dexmedetomidine decreases the sympathetically mediated presynaptic release of norepinephrine in the kidney [19], which could promote renal arterial vasodilatation. There are several limitations in this study. It is a retrospective analysis of a prospective study that has shown a relationship between dexmedetomidine infusion and enhanced renal function, but does not establish a cause and effect relationship. A pilot study at our institution shown that S Cr generally peaks approximately one to three days postoperatively and returns to baseline by day 7, so we limited the duration of observation to within this time frame. Only patients with normal preoperative renal function were enrolled in the study, although their average age was 66 years and presumably their renal reserve was somewhat compromised by the loss of glomerular filtration rate that occurs with aging [20]. No patients developed clinically significant renal dysfunction, but patients treated with placebo had a 20% increase from their baseline S Cr values, which may adversely effect outcome even without preexisting renal dysfunction [21]. Furthermore, because of the small number of patients enrolled, multivariate logistic regression analysis could not be performed to adjust for possible confounding factors such as nonsteroidal antiinflammatory drug use and fluid requirements. However, it reassuring in that these possible confounders were evenly distributed between groups. In this post hoc analysis of a prospective study, we have observed a significant association between dexmedetomidine infusion and enhanced renal function after thoracotomy, compared with placebo. Although we are unable to establish cause and effect, and our data do not suggest that it is related to increases in fluid administration, our observation is consistent with dexmedetomidine s known pharmacologic effects on antidiuretic and adrenergic responses. We are currently engaged in a prospective controlled trial that seeks to confirm these findings and establish a causative mechanism. References [1] Battafarano RJ, Piccirillo JF, Meyers BF, et al. 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